Beginning in 1982, a subset of the Pima Indians living in Southwestern Arizona, a population with one of the highest prevalence rates of obesity and type 2 diabetes mellitus (T2DM), has been studied to determine the etiologic risk factors that predispose non-diabetic individuals to develop T2DM. Within this high risk population, it is possible to identify subgroups of individuals at an even higher risk for T2DM, including persons whose mothers were diabetic during pregnancy. We use DXA scanning to determine body composition; MRI scanning to determine fat distribution; a 75-g oral glucose tolerance test to assess glucose tolerance; a hyperinsulinemic-euglycemic glucose clamp to assess insulin sensitivity; a 5-step hyperglycemic infusion to assess insulin secretory function. In the past year we have: a)established that normal glucose tolerant offspring of mothers with early onset diabetes manifest a defect in insulin secretion; b) identified novel risk factors for T2DM including relative hyperinsulinemia, large subQ abdominal adipocytes, and markers of subclinical chronic inflammation; c) studied the role of several adipocytokines as the possible link between obesity and T2DM; d)initiated a study of insulin secretory function in individuals whose mothers had diabetes during pregnancy, individuals whose fathers developed diabetes at an early age and individuals whose parents developed diabetes at a late age or did not develop diabetes; e)initiated a study to establish the pathophysiological link between large subQ abdominal adipocytes and risk of T2DM